PROJECT SUMMARY Chronic HBV (CHB) infection in HIV infected patients is six times more likely to lead to chronic cirrhosis, end stage liver disease and hepatocellular carcinomas than the HIV negative population. Immunotherapies that improve HBV-specific immunity in HIV-negative patients with chronic hepatitis B (CHB) could reduce this risk but vaccine immunogenicity in HIV infected patients is significantly compromised due to persistent immune dysfunction in this population. As a result, HBV vaccines that are highly effective even in the setting of immune dysfunction are needed. To address this, we developed a novel vaccine platform capable of inducing strong immune responses even in immunodeficient individuals. HBV antigens (HBsAg, HBcAg) are fused to an antibody (Ab) specific for the pattern recognition receptor CD180/RP105 (anti-human CD180). Our preliminary results in mice and rhesus macaques show that our CD180 vaccine platform induces robust, polyfunctional T cell responses and antibody that exceed levels induced by traditional recombinant protein vaccines. This remarkable potency is achieved by activating Ag-specific B cells including immature B cells to become efficient Ag presenting cells (APCs) and CD180-based vaccines retain immunogenic potency even in immunodeficient mice lacking mature B cells. By circumventing traditional antigen presentation pathways, we propose that our HBV-?CD180 vaccine will overcome limitations of current HBV vaccines and induce strong HBV specific immune responses in immunodeficient HIV infected patients. We will investigate this hypothesis in a preclinical SIV macaque model for AIDS. Our aims will 1) determine the optimum immunization regimen to induce strong HBV specific antibody and CD4+ and CD8+ T cell responses in chronically SIV infected rhesus macaques receiving antiretroviral drug therapy and 2) Determine if co-administration of a checkpoint inhibtor enhances the immunogenicity of the lead CD180scAb-HBV vaccine regimen in ART treated SIV infected rhesus macaques. If successful, this work will support further development of the HBV-?CD180 vaccine platform for immunotherapy of chronic HBV in HIV infected patients.